The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages (reviewed in, e.g., Stinson, S. C., Chem Eng News, Sep. 28, 1992, pp. 46-79) include fewer side effects and greater potency of enantiomerically pure compounds.
Traditional methods of organic synthesis have often been optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: use of enantiomerically pure starting materials derived from natural sources (the so-called xe2x80x9cchiral poolxe2x80x9d), or resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates, which requires the use of resolving agents, may be inconvenient and time-consuming. Furthermore, resolution often means that the undesired enantiomer is discarded, thus wasting half of the material.
Epoxides are valuable intermediates for the stereocontrolled synthesis of complex organic compounds due to the variety of compounds which can be obtained by epoxide-opening reactions. For example, xcex1-amino alcohols can be obtained simply by opening of an epoxide with azide ion, and reduction of the resulting xcex1-azido alcohol (for example, by hydrogenation). The reaction of epoxides with other nucleophiles similarly yields functionalized compounds which can be converted to useful materials. A Lewis acid may be added to act as an epoxide-activating reagent.
The utility of epoxides has expanded dramatically with the advent of practical asymmetric catalytic methods for their synthesis (Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis. Ojima, I., Ed.: VCH: New York, 1993; Chapter 4.1. Jacobsen, E. N. Ibid. Chapter 4.2). In addition to epoxidation of prochiral and chiral olefins, approaches to the use of epoxides in the synthesis of enantiomerically enriched compounds include kinetic resolutions of racemic epoxides (Maruoka, K.; Nagahara, S.; Ooi, T.; Yamamoto, H. Tetrahedron Lett 1989, 30, 5607. Chen, X. -J.; Archelas, A.; Rurstoss, R. J Org Chem 1993, 58, 5528. Barili, P. L.; Berti, G.; Mastrorilli, E. Tetrahedron 1993, 49, 6263.)
A particularly desirable reaction is the asymmetric ring-opening of symmetrical epoxides, a technique which utilizes easily made achiral starting materials and can simultaneously set two stereogenic centers in the functionalized product. Although the asymmetric ring-opening of epoxides with a chiral reagent has been reported, in most previously known cases the enantiomeric purity of the products has been poor. Furthermore, many previously reported methods have required stoichiometric amounts of the chiral reagent, which is likely to be expensive on a large scale. A catalytic asymmetric ring-opening of epoxides has been reported (Nugent, W. A., J Am Chem Soc 1992, 114, 2768); however, the catalyst is expensive to make. Furthermore, good asymmetric induction ( greater than 90% e.e.) was observed only for a few substrates and required the use of a Lewis acid additive. Moreover, the catalytic species is not well characterized, making rational mechanism-based modifications to the catalyst difficult.
In one aspect of the present invention, there is provided a process for stereoselective chemical synthesis which generally comprises reacting a nucleophile and a chiral or prochiral cyclic substrate in the presence of a non-racemic chiral catalyst to produce a stereoisomerically enriched product. The cyclic substrate comprises a carbocycle or heterocycle having a reactive center susceptible to nucleophilic attack by the nucleophile, and the chiral catalyst comprises an asymmetric tetradentate or tridentate ligand complexed with a metal atom. In the instance of the tetradentate ligand, the catalyst complex has a rectangular planar or rectangular pyramidal geometry. The tridentate ligand-metal complex assumes a planar or trigonal pyramidal geometry. In a preferred embodiment, the ligand has at least one Schiff base nitrogen complexed with the metal core of the catalyst. In another preferred embodiment, the ligand provides at least one stereogenic center within two bonds of a ligand atom which coordinates the metal.
In general, the metal atom is a transition metal from Groups 3-12 or from the lanthanide series, and is preferably not in its highest state of oxidation. For example, the metal can be a late transition metal, such as selected from Group 5-12 transition metals. In preferred embodiments, the metal atom is selected from the group consisting of Cr, Mn, V, Fe, Co, Mo, W, Ru and Ni.
In preferred embodiments, the substrate which is acted on by the nucleophile and catalyst is represented by the general formula 118: 
in which
Y represents O, S, N(R50), C(R52)(R54), or has the formula A-B-C; wherein R50 is selected from the set comprising hydrogen, alkyls, acyls, carbonyl-substituted alkyls, carbonyl-substituted aryls, and sulfonyls; R52 and R54 each independently represent an electron-withdrawing group; A and C are independently absent, or represent a C1-C5 alkyl, O, S, carbonyl, or N(R50); and B is a carbonyl, a thiocarbonyl, a phosphoryl, or a sulfonyl; and
R30, R31, R32, and R33 independently represent an organic or inorganic substituent which forms a covalent bond with the C1 or C2 carbon atoms of 118, and which permit formation of a stable ring structure including Y. For instance, the substituents R30, R31, R32, and R33 each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7; or any two or more of the substituents R30, R31, R32, and R33 taken together form a carbocylic or heterocyclic ring having from 4 to 8 atoms in the ring structure. In this formula, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is an integer in the range of 0 to 8 inclusive. In certain embodiments, R30, R31, R32, and R33 are chosen such that the substrate has a plane of symmetry.
Exemplary cyclic substrates for the subject reactions include epoxides, aziridines, episulfides, cyclopropanes, lactones, thiolactones, lactams, thiolactams, cyclic carbonates, cyclic thiocarbonates, cyclic sulfates, cyclic anhydrides, cyclic phosphates, cyclic ureas, cyclic thioureas, and sultones.
In a preferred embodiment, the method includes combining a nucleophilic reactant, a prochiral or chiral cyclic substrate, and a non-racemic chiral catalyst as described herein, and maintaining the combination under conditions appropriate for the chiral catalyst to catalyze stereoselective opening of the cyclic substrate at the electrophilic atom by reaction with the nucleophilic reactant.
In preferred embodiments, the chiral catalyst which is employed in the subject reaction is represented by the general formula: 
in which
Z1, Z2, Z3 and Z4 each represent a Lewis base;
the C1 moiety, taken with Z1, Z3 and M, and the C2 moiety, taken with Z2, Z4 and M, each, independently, form a heterocycle;
R1, R2, Rxe2x80x21 and Rxe2x80x22 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached,
R40 and R41 each independently are absent, or represent one or more covalent substitutions of C1 and C2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached,
or any two or more of the R1, R2, Rxe2x80x21, Rxe2x80x22 R40 and R41 taken together form a bridging substituent;
with the proviso that C1 is substituted at at least one site by R1, Rxe2x80x21 or R41, and C2 is substituted at at least one site by R2, Rxe2x80x22 or R40, and at least one of R1, Rxe2x80x21, and R41 is taken together with at least one of R2, Rxe2x80x22 and R40 to form a bridging substituent so as to provide Z1, Z2, Z3 and Z4 as a tetradentate;
M represents the transition metal; and
A represents a counterion or a nucleophile,
wherein each R1, R2, Rxe2x80x21, Rxe2x80x22 R40 and R41 are selected to provide at least one stereogenic center in the tetradentate ligand.
In exemplary embodiments, R1, R2, Rxe2x80x21 and Rxe2x80x22, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
each R40 and R41 occurring in 100 independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of nitrogen, oxygen, phosphorus, arsenic, and sulfur; and
m is an integer in the range of 0 to 8 inclusive.
For example, the catalyst can be represented by the general formula: 
in which
the substituents R1, R2, Y1, Y2, X1, X2, X3 and X4 each, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7,
or any two or more of the substituents taken together form a carbocycle or heterocycle ring having from 4 to 8 atoms in the ring structure,
with the proviso that at least one of R1, Y1, X1 and X2 is covalently bonded to at least one of R2, Y2, X3 and X4 to provide the xcex2-iminocarbonyls to which they are attached as a tetradentate ligand, and at least one of Y1 and Y2 is a hydrogen;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
m is an integer in the range of 0 to 8 inclusive;
M represents the transition metal; and
A represents a counterion or a nucleophile,
wherein each of the substituents R1, R2, Y1, Y2, X1, X2, X3 and X4, are selected such that the catalyst is asymmetric.
For example, a preferred class of catalysts are represented by the general formula: 
in which
the B1 moiety represents a diimine bridging substituent represented by xe2x80x94R15xe2x80x94R16xe2x80x94R17xe2x80x94, wherein R15 and R17 each independently are absent or represent an alkyl, an alkenyl, or an alkynyl, and R16 is absent or represents an amine, an imine, an amide, a phosphoryl, a carbonyl, a silyl, an oxygen, a sulfur, a sufonyl, a selenium, a carbonyl, or an ester;
each of B2 and B3 independently represent rings selected from a group consisting of cycloalkyls, cycloakenyls, aryls, and heterocyclic rings, which rings comprising from 4 to 8 atoms in a ring structure;
Y1 and Y2 each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
R12, R13, and R14 each independently are absent, or represent one or more covalent substitutions of B1, B2 and B3 with halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7, wherein R12 can occur on one or more positions of xe2x80x94R15xe2x80x94R16xe2x80x94R17xe2x80x94,
or any two or more of the R12, R13, R14, Y1 and Y2 taken together form a bridging substituent;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
m is an integer in the range of 0 to 8 inclusive;
M represents a transition metal; and
A represents a counterion or a nucleophile,
wherein R12, R13, R14, Y1 and Y2 are selected such that the catalyst is asymmetric.
In yet further preferred embodiments, the catalyst is a metallosalenate catalyst represented by the general formula: 
in which
each of the substituents R1, R2, R3, R4, R5, Y1, Y2, X1, X2, X3, X4, X5, X6, X7, and X8, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
or any two or more of the substituents taken together form a carbocycle or heterocycle having from 4 to 10 atoms in the ring structure;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
m is an integer in the range of 0 to 8 inclusive;
M represents a transition metal; and
A represents a counterion or a nucleophile;
wherein if R5 is absent, at least one of R1 and R2 is taken together with at least one of R3 and R4 to form a bridging substituent, and each of the substituents of 106 are selected such that the salenate is asymmetric.
Alternatively, the catalyst may comprise a tridentate ligand, such as the catalysts represented by general formula 140: 
in which
Z1, Z2, and Z3 each represent a Lewis base;
the E1 moiety, taken with Z1, Z2 and M, and the E2 moiety, taken with Z2, Z3 and M, each, independently, form a heterocycle;
R80 and R81 each, independently, are absent, or represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7, or any two or more of the R80 and R81 substituents taken together form a bridging substituent;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
m is an integer in the range of 0 to 8 inclusive;
M represents a transition metal; and
A represents a counteranion or a nucleophile;
wherein the tridentate ligand is asymmetric.
As described herein, the subject method can be used for carrying out enantioselective ring openings, diastereoselective ring openings (including kinetic resolutions), and stereoselective ring expansions of cyclic compounds.